Dipyridamole Inhibits Lipogenic Gene Expression by Retaining SCAP-SREBP in the Endoplasmic Reticulum

Esquejo, Ryan M.; Roqueta‐Rivera, Manuel; Shao, Wei; Phelan, Peter E.; Seneviratne, Uthpala; Ende, Christopher W. am; Hershberger, Paul; Machamer, Carolyn E.; Espenshade, Peter J.; Osborne, Timothy F.

doi:10.1016/j.chembiol.2020.10.003

Cited by 17 publications

(8 citation statements)

References 45 publications

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“…Betulin, an abundant compound in birch bark, suppresses proteolytic SREBP processing 28 . Dipyridamole, a phosphodiesterase inhibitor, blocks the ER-to-Golgi transport of the SCAP–SREBP complex independently of its phosphodiesterase inhibitor activity 29 . We have previously reported that XN, the most abundant prenylated flavonoid in hops, impairs the ER-to-Golgi translocation of the SCAP–SREBP complex by binding to Sec23/24 and blocking SCAP/SREBP incorporation into common coated protein II vesicles 18 .…”

Section: Discussionmentioning

confidence: 99%

Sulforaphane suppresses the activity of sterol regulatory element-binding proteins (SREBPs) by promoting SREBP precursor degradation

Miyata

Kodaka

Kikuchi

et al. 2022

Sci Rep

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Sterol regulatory element-binding proteins (SREBPs) are transcription factors that regulate various genes involved in cholesterol and fatty acid synthesis. In this study, we describe that naturally occurring isothiocyanate sulforaphane (SFaN) impairs fatty acid synthase promoter activity and reduces SREBP target gene (e.g., fatty acid synthase and acetyl-CoA carboxylase 1) expression in human hepatoma Huh-7 cells. SFaN reduced SREBP proteins by promoting the degradation of the SREBP precursor. Amino acids 595–784 of SREBP-1a were essential for SFaN-mediated SREBP-1a degradation. We also found that such SREBP-1 degradation occurs independently of the SREBP cleavage-activating protein and the Keap1-Nrf2 pathway. This study identifies SFaN as an SREBP inhibitor and provides evidence that SFaN could have major potential as a pharmaceutical preparation against hepatic steatosis and obesity.

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Section: Discussionmentioning

confidence: 99%

Sulforaphane suppresses the activity of sterol regulatory element-binding proteins (SREBPs) by promoting SREBP precursor degradation

Miyata

Kodaka

Kikuchi

et al. 2022

Sci Rep

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“…Moreover, immunofluorescence analysis of ERK1/2 activation confirmed that dipyridamole induced the phosphorylation of ERK1/2, which was abolished by the A 2A R antagonist SCH58261. Evidence in the literature already demonstrated that dipyridamole can exert its activity in a cAMP-independent way [ 46 ]; this interesting paper investigated the mechanism of action of dipyridamole for its known ability to inhibit lipogenic gene expression by blocking the maturation of sterol regulatory element-binding proteins (SREBPs); SREBPs are key regulators of the expression of genes coding for enzymes required for the synthesis of triglycerides and cholesterol. In their paper, the authors concluded that the above-mentioned effect was not depending on cAMP, but they did not investigate other cellular signaling (e.g., that elicited by A 2A R).…”

Section: Discussionmentioning

confidence: 99%

Repurposing Dipyridamole in Niemann Pick Type C Disease: A Proof of Concept Study

Pepponi

Simone

Nuccio

et al. 2022

IJMS

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Niemann Pick type C disease (NPC) is a rare disorder characterized by lysosomal lipid accumulation that damages peripheral organs and the central nervous system. Currently, only miglustat is authorized for NPC treatment in Europe, and thus the identification of new therapies is necessary. The hypothesis addressed in this study is that increasing adenosine levels may represent a new therapeutic approach for NPC. In fact, a reduced level of adenosine has been shown in the brain of animal models of NPC; moreover, the compound T1-11, which is able to weakly stimulate A2A receptor and to increase adenosine levels by blocking the equilibrative nucleoside transporter ENT1, significantly ameliorated the pathological phenotype and extended the survival in a mouse model of the disease. To test our hypothesis, fibroblasts from NPC1 patients were treated with dipyridamole, a clinically-approved drug with inhibitory activity towards ENT1. Dipyridamole significantly reduced cholesterol accumulation in fibroblasts and rescued mitochondrial deficits; the mechanism elicited by dipyridamole relies on activation of the adenosine A2AR subtype subsequent to the increased levels of extracellular adenosine due to the inhibition of ENT1. In conclusion, our results provide the proof of concept that targeting adenosine tone could be beneficial in NPC.

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“…More recent discoveries uncovered the heterogeneity of metabolic reprogramming in cancer cells to also include increases in oxidative phosphorylation and the use of alternative carbon sources (i.e., glutamine, fatty acids, and serine). Various studies have revealed a metabolic regulation system between cancer cells, immune cells, and stroma and have demonstrated the targetability of these metabolic shifts in preventing disease progression (151)(152)(153)(154)(155)(156)(157)(158). Surprisingly, studies have also revealed regulation and correlation between metabolic shifts and cytoskeletal proteins in cancer.…”

Section: Targeting Cytoskeletal and Metabolic Connectionsmentioning

confidence: 99%

Pancreatic Ductal Adenocarcinoma Cortical Mechanics and Clinical Implications

et al. 2022

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Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers due to low therapeutic response rates and poor prognoses. Majority of patients present with symptoms post metastatic spread, which contributes to its overall lethality as the 4th leading cause of cancer-related deaths. Therapeutic approaches thus far target only one or two of the cancer specific hallmarks, such as high proliferation rate, apoptotic evasion, or immune evasion. Recent genomic discoveries reveal that genetic heterogeneity, early micrometastases, and an immunosuppressive tumor microenvironment contribute to the inefficacy of current standard treatments and specific molecular-targeted therapies. To effectively combat cancers like PDAC, we need an innovative approach that can simultaneously impact the multiple hallmarks driving cancer progression. Here, we present the mechanical properties generated by the cell’s cortical cytoskeleton, with a spotlight on PDAC, as an ideal therapeutic target that can concurrently attack multiple systems driving cancer. We start with an introduction to cancer cell mechanics and PDAC followed by a compilation of studies connecting the cortical cytoskeleton and mechanical properties to proliferation, metastasis, immune cell interactions, cancer cell stemness, and/or metabolism. We further elaborate on the implications of these findings in disease progression, therapeutic resistance, and clinical relapse. Manipulation of the cancer cell’s mechanical system has already been shown to prevent metastasis in preclinical models, but it has greater potential for target exploration since it is a foundational property of the cell that regulates various oncogenic behaviors.

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Dipyridamole Inhibits Lipogenic Gene Expression by Retaining SCAP-SREBP in the Endoplasmic Reticulum

Cited by 17 publications

References 45 publications

Sulforaphane suppresses the activity of sterol regulatory element-binding proteins (SREBPs) by promoting SREBP precursor degradation

Sulforaphane suppresses the activity of sterol regulatory element-binding proteins (SREBPs) by promoting SREBP precursor degradation

Repurposing Dipyridamole in Niemann Pick Type C Disease: A Proof of Concept Study

Pancreatic Ductal Adenocarcinoma Cortical Mechanics and Clinical Implications

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